Treating rare disease: Niemann-Pick disease type C

Niemann-Pick disease type C (NPC) is a rare, inherited neurodegenerative disorder caused by an intracellular lipid-trafficking defect. Although the disease can present at any age — from before birth to late middle age — about half of those affected have signs and symptoms before age 10. While NPC is a progressive disease, early diagnosis and treatment can improve quality and duration of life.

Mayo Clinic in Rochester, Minn., is one of the few centers in the world with experience diagnosing and treating patients with NPC. In collaboration with the National Institutes of Health (NIH), Mayo also is at the forefront of research into the genetics of the disease as well as efforts to improve patient care.

"Even though we don't have a disease-modifying therapy, quality of life and survival have improved for these patients over the last quarter century," says Marc C. Patterson, M.D., chair of Child and Adolescent Neurology at Mayo in Minnesota." There is no known cure, but we can treat patients. The sooner we are able to diagnose and start treatment, the better the outcome."

NPC results from mutations in the NPC1 or NPC2 genes, which encode proteins involved in the movement of lipids within cells. The malfunctioning proteins cause lipids to accumulate in cells — free cholesterol in peripheral tissues and gangliosides in neurons.

The disease can present in utero, with ultrasound examination detecting an enlarged liver and spleen and fluid in the fetal abdomen. Infants may present with profound jaundice or liver failure. These early cases are often fatal.

Beyond infancy, NPC is predominantly a neurological disease. Younger children may present with developmental delays and low muscle tone. Older children are more likely to have problems with gait, balance, coordination, dystonia, spasticity, speech, swallowing and cognitive impairment, all of which worsen over time. Teenagers and adults often present with those problems as well as psychiatric symptoms or early-onset dementia.

Characteristic early sign

Dr. Patterson notes that one of the most important early signs of NPC is problems with vertical supranuclear gaze. "It can be very subtle at first and is almost always missed," he says. "But children who are having difficulty with rapid vertical eye movement may blink, then jerk their heads up or down to generate a reflex to move their eyes vertically. In our experience, vertical supranuclear gaze is the first neurological sign of Niemann-Pick C. Examining for it gives the best chance of diagnosing the disease early."

In addition, about one-third to one-half of patients have seizures that can be difficult to control. Up to a third of that group can have gelastic cataplexy, a sudden loss of muscle tone triggered by feeling amused. "In severe cases, if anything amuses these children, they collapse to the floor," Dr. Patterson says. "It can be quite disabling."

A definitive diagnosis of NPC requires biochemical analysis of a skin biopsy. Mayo has one of the few labs in the U.S. capable of performing this test. The Mayo lab can also analyze blood samples to look for mutations on the NPC1 or NPC2 genes. About 95 percent of NPC cases are due to NPC1 mutations. Dr. Patterson was part of an NIH team that identified NPC1 in 1997; NPC2 involvement was discovered in 2000.

Novel therapies and research

Although NPC is a devastating progressive disease, medication can ease symptoms such as seizures and spasticity. When swallowing problems become severe, patients can be prescribed enteral nutrition. "The huge challenge, as in many other neurodegenerative diseases, is that by the time you make the diagnosis, there's such a significant burden of disease that your opportunity to improve the outcome is limited," Dr. Patterson says.

Dr. Patterson was the principal investigator in trials of miglustat, a novel small-molecule therapy that can slow the progression of NPC for a limited time. Based on that work, miglustat has been approved for the treatment of NPC in more than 40 countries, although not in the U.S.

Other research efforts include longitudinal studies of cognitive changes in NPC patients. Dr. Patterson chairs a scientific advisory committee that is developing an international database for NPC. Mayo also is a participant in the Lysosomal Disease Network, part of the NIH-funded Rare Diseases Clinical Research Network. "In these ultrarare diseases, it's hard to get data," Dr. Patterson says. "You really need a big, international process. At Mayo we're involved in that effort."

May 21, 2014